Fenofibrate (2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid 1-methylethyl ester) is an approved substance for the treatment of hypercholesterolemia and hypertriglyceridemia. Fenofibrate is practically insoluble in water. It is normally poorly and variably absorbed in the fasted state and currently is prescribed to be taken with food.
Known fenofibrate dosage forms include Tricor® micronized tablets in which fenofibrate powder is co-micronized with a solid wetting agent such as sodium lauryl sulfate.
U.S. application Ser. No. 11/573,237 (Almarsson et al.) discloses liquid formulations for treating hypertriglyceridemia which comprise fenofibrate and a mixture of omega-3 oil, an alcohol, and, optionally, one or more surfactants. The disclosed formulations provide fenofibrate formulations in small volumes, due to the attained high concentration of fenofibrate.
The hypotriglyceridemic effects of omega-3 oils from fish oils are well established. Amounts both above and below about 1 gram per day of omega-3 oils from fish oil have been shown to decrease serum triglyceride concentrations by about 25% to about 40%, decrease VLDL blood plasma levels, and to increase both LDL and HDL plasma levels (See e.g., Harris, William S, Clin. Cardiol. 22, (Suppl. II), II-40-II-43 (1999)).
Additionally, it has been clear for several decades that elevated blood cholesterol is a major risk factor for coronary heart disease (CHD), and many studies have shown that the risk of CHD events can be reduced by lipid-lowering therapy. Prior to 1987, the lipid-lowering armamentarium was limited essentially to a low saturated fat and cholesterol diet, the bile acid sequestrants (cholestyramine and colestipol), nicotinic acid (niacin), the fibrates and probucol. Unfortunately, all of these treatments have limited efficacy or tolerability, or both. With the introduction of lovastatin (MEVACOR®; see U.S. Pat. No. 4,231,938), the first inhibitor of HMG-CoA reductase to become available for prescription in 1987, for the first time physicians were able to obtain comparatively large reductions in plasma cholesterol with very few adverse effects.
In addition to the natural fermentation products, mevastatin and lovastatin, there are now a variety of semi-synthetic and totally synthetic HMG-CoA reductase inhibitors, including simvastatin (ZOCOR®; see U.S. Pat. No. 4,444,784), pravastatin sodium salt (PRAVACHOL®; see U.S. Pat. No. 4,346,227), fluvastatin sodium salt (LESCOL®; see U.S. Pat. No. 5,354,772), atorvastatin calcium salt (LIPITOR®; see U.S. Pat. No. 5,273,995) and cerivastatin sodium salt (also known as rivastatin; see U.S. Pat. No. 5,177,080). The HMG-CoA reductase inhibitors described above belong to a structural class of compounds which contain a moiety which can exist as either a 3-hydroxy lactone ring or as the corresponding ring opened dihydroxy open-acid, and are often referred to as “statins.”
Salts of the dihydroxy open-acid can be prepared, and in fact, as noted above, several of the marketed statins are administered as the dihydroxy open acid salt forms. In addition, several other statin salts have recently been observed (See US Application No. 20060034815, filed on Aug. 5, 2005).
A pharmaceutical formulation comprising the beneficial effects of fenofibrate, a statin, and omega-3 oil could enable both ease of administration and could improve patient compliance where both fenofibrate and a statin are suitable. In addition, the omega-3 oil may lead to even further therapeutic effect than with fenofibrate and a statin alone.
Ideally, such formulations would not exhibit any food effect, thereby providing health care providers and patients with a wide latitude in selecting convenient and effective antihypertriglyceridemic and antihypercholesterolemic dosage regimens.